This invention relates to novel pyrrolo[2,3-d]-pyrimidines useful for inflammatory diseases.
The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter called, xe2x80x9csPLA2xe2x80x9d) has been thoroughly described in two articles, namely, xe2x80x9cCloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluidxe2x80x9d by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5335-5338, 1989; and xe2x80x9cStructure and Properties of a Human Non-pancreatic Phospholipase A2xe2x80x9d by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA2; such as sepsis or rheumatoid arthritis.
It is desirable to develop new compounds and treatments for sPLA2 induced diseases.
This invention is a novel use of the class of compounds known as pyrrolo[2,3-d]pyrimidines to inhibit mammalian sPLA2 mediated release of fatty acids.
This invention Is also a novel class of pyrrolo[2,3-d]pyrimidines having potent and selective effectiveness as inhibitors of mammalian sPLA2.
This invention is also a pyrrolo[2,3-d]pyrimidine compound in the treatment of Inflammatory Disease.
This invention is also pharmaceutical compositions containing the pyrrolo[2,3-d]pyrimidines of the invention.
This invention is also a method of preventing and treating Inflammatory Diseases in mammals by contact with a therapeutically effective amount of the pyrrolo[2,3-d]pyrimidines of the invention.
This invention is also the use, in the manufacture of a medicament of pyrrolo[2,3-d]pyrimidine compound as an active ingredient in an sPLA2 inhibiting composition in admixture with an inert carrier.
Definitions
The term, xe2x80x9cInflammatory Diseasesxe2x80x9d refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter""s syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with xe2x80x9cvasculitic syndromesxe2x80x9d, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec""s granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo gout, non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat""s Disease, systemic lupus erythrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.
The term, xe2x80x9cpyrrolo[2,3-d]pyrimidine nucleusxe2x80x9d refers to a nucleus (having numbered positions)with the structural formula (X): 
The pyrrolo[2,3-d]pyrimidine compounds of the invention employ certain defining terms as follows:
The term, xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl.
The term, xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms means a straight chain or branched monovalent hydrocarbon group having the stated number range of carbon atoms, and typified by groups such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers.
The term, xe2x80x9chydrocarbylxe2x80x9d means an organic group containing only carbon and hydrogen.
The term, xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo, or iodo.
The term, xe2x80x9cheterocyclic radicalxe2x80x9d, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, pyrrolodinyl, piperidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrahydrothiopheneyl, pentamethylenesulfadyl, 1,3-dithianyl, 1,4-dithianyl, 1,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl and quinoxalinyl.
The term, xe2x80x9ccarbocyclic radicalxe2x80x9d refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, thiophenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluoyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a): 
where n is a number from 1 to 8.
The term, xe2x80x9cnon-interfering substituentxe2x80x9d, refers to radicals suitable for substitution at the 2 position of the pyrrolo[2,3-d]pyrimidine nucleus and on other nucleus substituents (as hereinafter described for Formula I), infra. Illustrative non-interfering radicals are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluoyl, xylenyl, biphenyl, C1-C8 alkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C2xe2x80x94C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C1-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C8 alkylthio, C2-C12 alkylthiocarbonyl, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C1-C8 haloalkoxy, C1-C8 haloalkylsulfonyl, C1-C8 haloalkyl, xe2x80x94CF3, C1-C8 hydroxyalkyl, xe2x80x94C(O)O(C1-C8 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C8 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and C1-C8 carbonyl; where n is from 1 to 8.
The term, xe2x80x9c(acidic group)xe2x80x9d means an organic group which when attached to a pyrrolo[2,3-d]pyrimidine nucleus, through suitable linking atoms (hereinafter defined as the xe2x80x9cacid linkerxe2x80x9d), acts as a proton donor capable of hydrogen bonding. Illustrative of an (acidic group) are the following:
-5-tetrazolyl,
xe2x80x94SO3H,

where n is 1 to 8, R41 is a metal or C1-C8 alkyl.
The words, xe2x80x9cacid linkerxe2x80x9d refer to a divalent linking group symbolized as, xe2x80x94(La)xe2x80x94, which has the function of joining the 4 or 5 position of the pyrrolo[2,3-d]pyrimidine nucleus to an acidic group in the general relationship: 
The words, xe2x80x9cacid linker lengthxe2x80x9d, refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group xe2x80x94(La)xe2x80x94 that connects the 4 position of the pyrrolo[2,3-d]pyrimidine nucleus with the acidic group. The presence of a carbocyclic ring in xe2x80x94(La)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of xe2x80x94(La)xe2x80x94. Illustrative acid linker groups are; 
wherein, groups (a), (b), and (c) have acid linker lengths of 5, 7, and 2, respectively.
The term, xe2x80x9caminexe2x80x9d, includes primary, secondary and tertiary amines.
The terms, xe2x80x9cmammalxe2x80x9d and xe2x80x9cmammalianxe2x80x9d include human.
The term, xe2x80x9calkylene chain of 1 or 2 carbon atomsxe2x80x9d refers to the divalent radicals, xe2x80x94CH2xe2x80x94CH2xe2x80x94 and xe2x80x94CH2xe2x80x94.
The term, xe2x80x9cgroup containing 1 to 4 non-hydrogen atomsxe2x80x9d refers to relatively small groups which form substituents at the 6 position of the pyrrolo[2,3-d]pyrimidine nucleus, said groups may contain non-hydrogen atoms alone, or non-hydrogen atoms plus hydrogen atoms as required to satisfy the unsubstituted valence of the non-hydrogen atoms, for example; (i) groups absent hydrogen which contain less than 4 non-hydrogen atoms such as xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO3; and (ii) groups having hydrogen atoms which contain less than 4 non-hydrogen atoms such as xe2x80x94CH3, xe2x80x94C2H5, and xe2x80x94CHxe2x95x90CH2.
The Pyrrolo[2,3-d]pyrimidine Compounds of the Invention
The compounds of the invention have the general formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof; 
wherein;
R2 is selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituent(s), heterocyclic radicals, and heterocyclic radical substituted with non-interfering substituent(s);
R4 is xe2x80x94(L4)-(acidic group); wherein xe2x80x94(L4)xe2x80x94, is a divalent acid linker having an acid linker length of 1 to 4;
R5 is xe2x80x94(L5)xe2x80x94Z, where xe2x80x94(L5)xe2x80x94 is a divalent linker group selected from a bond or a divalent group selected from: 
and Z is selected from acetamide, thioacetamide, glyoxylamide, thioglyoxylamide, hydrazide or thiohydrazide groups represented by the formulae, 
where
R51 and R52 are independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C4 cycloalkyl, and X is oxygen or sulfur;
R6 is hydrogen, or a group containing 1 to 4 non-hydrogen atoms plus any required hydrogen atoms;
R7 is selected from groups (a), (b) and (c) wherein;
(a) is C7-C20 alkyl, C7-C20 haloalkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one on more independently selected non-interfering substituents; or
(c) is the group xe2x80x94(L7)xe2x80x94R71; where, xe2x80x94(L7)xe2x80x94 is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur; wherein the combination of atoms in xe2x80x94(L7)xe2x80x94 is selected from the group consisting of (i) carbon and hydrogen only, (ii) sulfur only, (iii) oxygen only, (iv) nitrogen and hydrogen only, (v) carbon, hydrogen, and sulfur only, and (vi) and carbon, hydrogen, and oxygen only; and where R71 is a group selected from (a) or (b).
Preferred Subgroups of Compounds of Formula (I)
I. Preferred R2 Substituents
R2 is preferably selected from the group consisting of hydrogen, cyclopropyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C1-C8 alkylsulfonyl, C1-C12 alkylamino, phenyl, and thiophenyl. Particularly preferred R2 groups are hydrogen, methyl, ethyl, propyl, isopropyl, xe2x80x94Sxe2x80x94CH3, xe2x80x94Sxe2x80x94C2H5, methylsulfonyl, ethylsulfonyl, thiophenyl, dimethylamino, diethylamino, ethylamino, methoxy, and ethoxy.
II. Preferred R4 Substituents
A preferred subclass of compounds of formula (I) are those wherein R4 is a substituent having an acid linker with an acid linker length of 2 or 3 and the acid linker group, xe2x80x94(L4)xe2x80x94, is selected from a group represented by the formula; 
where Q1 is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94, and 
and where R40 is independently selected from hydrogen, C1-C8 alkyl, aryl, C1-C8 alkaryl, C1-C8 alkoxy, aralkyl, and halo. Most preferred are compounds are those where the acid linker, xe2x80x94(L4)xe2x80x94, for R4 is selected from the groups; 
where R40 is hydrogen or C1-C8 alkyl. Preferred as the (acidic group) in the group R4 are acidic groups selected from:
-5-tetrazolyl,
xe2x80x94SO3H, 
where R41 is a metal or C1-C8 alkyl. A salt or prodrug derivative of the (acidic group) is also suitable.
Examples of salt derivatives of the (acidic group) R4 are; 
Examples of ester prodrug derivatives are of the (acidic group) R4; 
Particularly preferred are (acidic groups) selected from:
xe2x80x94CO2H
xe2x80x94SO3H
xe2x80x94P(O)(OH)2
and salt, and prodrug (e.g., ester, amide) derivatives thereof.
The most preferred acidic group in the compounds of the invention is a carboxylic acid group, xe2x80x94CO2H.
Preferred R5 Substituents
A preferred subclass of compounds of formula (I) are those wherein all X""s of group R5 are oxygen.
Another preferred subclass of compounds of formula (I) are those wherein Z is a group selected from acetamide, glyoxylamide, or hydrazide, represented by the formulae (Va), (Vb), and (Vc); 
Most preferred are compounds of formula (I) wherein R5 is the glyoxylamide group represented by the formula; 
For the group R5 it is preferred that linking group xe2x80x94(L5)xe2x80x94 be a bond, particularly when the R5 is a bond in combination with Z being the glyoxylamide group.
Preferred R6 Substituents
Another preferred subclass of compounds of formula (I) are those wherein R6 is selected from the group; hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl and halo.
Preferred R7 Substituents
Another preferred subclass of compounds of formula (I) wherein the divalent linking group xe2x80x94(L7)xe2x80x94 is selected from the formulae (VIIa), (VIIb), (VIIc), (VIId), (VIIe), and (VIIf): 
where Q2 is a bond or any of the divalent groups (VIIa), (VIIb), (VIIc), (VIId), (VIIe), and (VIIf) and each R70 is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 alkoxy.
Particularly preferred as the linking group xe2x80x94(L7)xe2x80x94 of R7 is an alkylene chain of 1 or 2 carbon atoms, namely, xe2x80x94(CH2)xe2x80x94, and xe2x80x94(CH2xe2x80x94CH2)xe2x80x94.
The preferred group for R71 is a substituted or unsubstituted group selected from the group consisting of C5xe2x80x94C14 cycloalkyl, C5-C14 cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluoyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a); 
where n is a number from 1 to 8.
Substituents for R71 are non-interfering radicals selected from halo, xe2x80x94CF3, C1-C10 alkyl, C1-C10 alkoxy, xe2x80x94Sxe2x80x94(C1-C10 alkyl), and C1-C10 haloalkyl radicals. Particularly preferred are compounds wherein for R7 the combined group xe2x80x94(L7)xe2x80x94R71 is selected from the group consisting of 
where R72 is a radical independently selected from hydrogen, halo, xe2x80x94CF3, C1-C10 alkyl, C1-C10 alkoxy, xe2x80x94Sxe2x80x94(C1-C10 alkyl), and C1-C10 haloalkyl, C1-C10 hydroxyalkyl and t is a number from 0 to 5 and u is a number from 0 to 4.
Preferred compounds of the invention are those having the general formula (II), or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; 
wherein;
R12 is selected from hydrogen, halo, cyclopropyl, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio C1-C8 haloalkyl, C1-C8 hydroxyalkyl, phenyl, thiophenyl, thiomethyl, diethylamino, dimethylamino, and ethylamino.
xe2x80x94(L4)xe2x80x94 is a divalent group selected f rom 
where R40 is hydrogen C1-C8 alkyl.
R16 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, C1-C3 alkoxy, C1-C3 alkylthio, and C1-C3 haloalkyl.
R72 is and C1-C8 alkyl, C1-C8 alkoxy, xe2x80x94Sxe2x80x94(C1-C8 alkyl), C1-C8 haloalkyl, C1-C8 hydroxyalkyl, xe2x80x94CF3,and halo, phenyl, biphenyl, thiophenyl and t is an integer from 0 to 5. Preferred R72 substituents are xe2x80x94Cl, xe2x80x94CF3, and xe2x80x94F located at a position meta to the linking group attached to the nitrogen atom at the 7 position, for example, as shown in Formula IIa below; 
One set of specific preferred compounds and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof which are illustrative of the compounds of the invention include the following: 
Another set of specific preferred compounds and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof which are illustrative of the compounds of the invention include the following:
Y. [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester,
Z. [[2-(phenylthio)-5-(aminooxoacetyl)-6-ethyl -7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester,
AA. [[2-(phenylthio)-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid,
AB. [[2-methoxy-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester,
AC. [[2-methoxy-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy] acetic acid,
AF. [[5-(aminooxoacetyl)-6-ethyl-7-([1,1xe2x80x2-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester,
AG. [[5-(aminooxoacetyl)-6-ethyl-7-([1,1xe2x80x2-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid,
AK. [[5-(aminooxoacetyl)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester,
AL. [[5-(aminooxoacetyl)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid,
AN. [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-([1,1xe2x80x2-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester,
AO. [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-([1,1xe2x80x2-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid,
AP. [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester,
AQ. [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid,
AR. [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester,
AS. [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid,
AT. [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester,
AU. [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid,
AY. [[5-(aminooxoacetyl)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester,
AZ. [[5-(aminooxoacetyl)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid,
BD. [[5-(aminooxoacetyl)-6-ethyl-7-[[3-trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester,
BE. [[5-(aminooxoacetyl)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid,
BDA.[[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[[2-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester, and
BDB. [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[[2-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid.
The salts of the above pyrrolo[2,3-d]pyrimidine compounds represented by formulae (I) and (II) are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic or basic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin. For example, the (acidic group) of the substituent R4 of Formula I may be selected as xe2x80x94CO2H and salts may be formed by reaction with appropriate bases (e.g., NaOH, KOH) to yield the corresponding sodium and potassium salt.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, bromide, chloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, malseate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.
Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans-isomeric forms of the compounds. The R- and S-isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans-isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers and diastereomers, because they have different melting points, different boiling points, and different solubilities can be separated by conventional means, such as crystallization.
Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred esters as prodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N-diethylglycolamido.
N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-chloro-N,N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).
Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).
Method of Making the Compounds of the Invention
The synthesis of the pyrrolo[2,3-d]pyrimidines of the invention (viz., Compounds of Formula I) can be accomplished by well known methods as recorded in the chemical literature. Those procedures useful for the syntheses of the compounds of the invention are illustrated herein and outlined in the following reaction Scheme 1 
Ethylcyano acetate compound III was alkylated with 1-bromo-2-butanone to provide compound IV. The ethyl group of the ketone eventually becomes the ethyl substituent at the 6 position of the pyrrolopyrimidine. The ketone is treated with an alcohol under mildly acidic conditions generating a ketal, compound V. Compound V can then be reacted under basic to neutral conditions with ureas, thioureas, and amidines. For example, compound V can be reacted with thiourea under basic conditions to provide compound VIa, 2-thiopyrimidone. The thio group can be hydrogenolized using Raney Nickel to provide the 2-unsubstituted pyrimidone. Likewise, compound V can be reacted under neutral conditions with acetamidine to provide the 2-methylpyrimidone, compound VIc. Compound VI can be cyclized to a pyrrolopyrimidine compound VII, and reacted with POCl3 to produce the 2-substituted 4-chloropyrrolpyrimidine, compound VIII. The nitrogen at the 7 position is then alkylated under basic conditions and the chloride displaced with enough glycolate to provide compound X. The glyoxamide side chain was incorporated using an excess of oxalyl chloride in the presence of pyridine followed by quench with ammonia. This provides the compound of the invention, (C2), supra. Straightforward hydrolysis of the methyl ester followed by acidification provides compound I (C4) supra. The sulfur group can be oxidized and displaced with a variety of nucleophiles which is described at the bottom as going from compound IId, to compound XI, to compound IIx.
Methods of Using the Compounds of the Invention
Pyrrolo[2,3-d]pyrimidines described herein are believed to achieve their beneficial therapeutic action principally by direct inhibition of mammalian (including human) sPLA2, and not by acting as antagonists for arachidonic acid, nor other active agents below arachidonic acid in the arachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, and etc.
The method of the invention for inhibiting sPLA2 mediated release of fatty acids comprises contacting mammalian sPLA2 with an therapeutically effective amount of pyrrolo[2,3-d]pyrimidines corresponding to Formulae (I) or (II) as described herein including salt or a prodrug derivative thereof.
Another aspect of this invention is a method for treating Inflammatory Diseases such as inflammatory bowel disease, septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, osteoarthritis, and related diseases which comprises administering to a mammal (including a human) a therapeutically effective dose pyrrolo[2,3-d]pyrimidines of the invention (see, formulae I and II).
As previously noted the compounds of this invention are useful for inhibiting sPLA2 mediated release of fatty acids such as arachidonic acid. By the term, xe2x80x9cinhibitingxe2x80x9d is meant the prevention or therapeutically significant reduction in release of sPLA2 initiated fatty acids by the compounds of the invention. By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention.
Preferably compounds of the invention (per Formulae I or II) or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of Active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.
The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the pyrrolo[2,3-d]pyrimidines of the invention together with a pharmaceutically acceptable carrier or diluent therefor. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
In making the compositions of the present invention, the Active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration.
For the pharmaceutical formulations any suitable carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. For example, for intravenous injection the compounds of the invention may be dissolved in at a concentration of 2 mg/ml in a 4% dextrose/0.5% Na citrate aqueous solution. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc.
In powders the carrier is a finely divided solid which is in admixture with the finely divided Active ingredient. In tablets the Active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the Active ingredient which is the novel compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.
Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs.
The Active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The Active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the finely divided Active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
The following pharmaceutical formulations 1 thru 8 are illustrative only and are not intended to limit the scope of the invention in any way. xe2x80x9cActive ingredientxe2x80x9d, refers to a compound according to Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Hard gelatin capsules are prepared using the following ingredients:
The components are blended and compressed to form tablets each weighing 665 mg
An aerosol solution is prepared containing the following components:
The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to xe2x88x9230xc2x0 C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
Tablets, each containing 60 mg of Active ingredient, are made as follows:
The Active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Capsules, each containing 80 mg of Active ingredient, are made as follows:
The Active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
Suppositories, each containing 225 mg of Active ingredient, are made as follows:
The Active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
Suspensions, each containing 50 mg of Active ingredient per 5 ml dose, are made as follows:
The Active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
An intravenous formulation may be prepared as follows:
The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.
All of the products of the Examples described below as well as intermediates used in the following procedures showed satisfactory nmr and ir spectra. They also had the correct mass spectral values.